JP7439084B2 - Novel carrier particles for dry powder formulations for inhalation - Google Patents

Description

The present invention relates to carrier particles for use in dry powder formulations for inhalation and processes for their preparation.

Dry powder inhalation (DPI) medications have been used for many years to treat respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and systemic diseases.
Compared to oral administration, the first stage of metabolism is bypassed or significantly reduced, allowing effective treatment with relatively small doses.
Such small doses can reduce the amount of drug exposure in the body and minimize side effects. Local administration to the lungs also reduces systemic side effects because the drug reaches the site of action directly. Reducing dosages can also significantly reduce costs, especially when expensive therapeutics are involved.

Particle sizes of several micrometers, typically 1-5 microns, are required for effective delivery to the lungs.
Dry powder formulations are usually formulated by mixing the drug with coarse carrier particles, and the finely divided active particles adhere to the surface of the carrier particles in an inhalation device, forming an ordered mixture. .
The carrier weakens the cohesive force of the fine powder, improves its fluidity, and facilitates handling during manufacturing processes (pouring, filling, dosing, etc.).
Additionally, the carrier acts as a bulking agent when the therapeutic dose of the drug is in the microgram range.

During inhalation, drug particles separate from the surface of the carrier particles and penetrate into the lower lungs, while larger carrier particles are mostly deposited in the oropharyngeal cavity.
Detachment of drug particles from the carrier surface is considered the most important factor governing drug availability to the lungs.
This depends on the mechanical stability of the powder mixture and how this is influenced by the adhesive properties between the drug and the carrier and the external forces required to break the non-covalent bonds formed between the adhered particles. do.
Too strong a bond between adhered particles can actually prevent separation of the finely divided drug particles from the surface of the carrier particles.
Various approaches have been proposed in the art aimed at modulating adhesion in order to enhance the release of drug particles from carrier particles and thus increase the respirable fraction.

For example, in order to meet the above objectives, the addition of fine excipient particles and/or fine additives (hereinafter collectively referred to as fine particles) having lubricant or anti-adhesion properties has been proposed as a solution to the technical problem. ing.
Typically, the microparticles have a size of less than 50 microns, preferably less than 20 microns.
However, since microparticles have poor flowability, as the content of microparticles increases, the flowability properties of the associated powder formulation tend to deteriorate.

On the other hand, the inhalation route is increasingly utilized for active ingredients administered in rather high single doses.
This means that the higher the dose and therefore the concentration of the active ingredient, the better the possibility of achieving a better homogeneity of the distribution of the drug in the powder mixture, and therefore the better the possibility of achieving a good homogeneity of the distribution of the drug in the powder mixture, as well as its proper disaggregation during inhalation by the patient. as it is well known that there is an increased risk of forming inhomogeneous agglomerates (i.e., micronized drug particles held together by strong cohesive forces), which is detrimental to the possibility of achieving good accuracy. , is becoming a difficult challenge.
Furthermore, the higher the dose and therefore the concentration of active ingredient, the higher the number of microparticles that may be necessary to have a sufficient respirable fraction.

Large amounts of micronized active ingredients and/or fine excipient particles can have a detrimental effect on the flow properties of the associated formulations, thus making it difficult to deliver the correct dose upon activation of the inhaler. This will affect the ability of the equipment to
It would therefore be advantageous to provide carrier particles that can accommodate significantly larger amounts of micronized drug without compromising the flow properties of the associated powder formulation.
It would be further advantageous to provide carrier particles that can accommodate significant amounts of micronized drug while maintaining good aerosol performance without the use of fine excipient particles and/or fine additives.
The problem is solved by the carrier particles of the present invention and the method for preparing them.

In a first aspect, the invention provides:
Melt-spray solidified particles (i.e., spray congealed) made of mannitol used as a carrier for dry powder formulations for inhalation, said particles ranging from 10 to 300 μm. having a mass diameter of , said particles have a shape factor ( spray congealed particles characterized by a regular shape expressed by a shape factor.

In a second aspect, the invention provides:
Said carrier particles obtainable by a method comprising the following steps:
i) heating the mannitol until completely melted;
ii) spraying molten mannitol into a spray congealing chamber by a suitable pressure nozzle to obtain droplets;
iii) cooling the droplets to induce solidification and particle formation;
iv) separating the obtained particles;
v) subjecting the particles to a conditioning step;
is directed towards.

In a third aspect, the invention provides:
The above carrier particles obtained by a method comprising the following steps:
i) heating the mannitol until completely melted;
ii) spraying molten mannitol into a spray congealing chamber by a suitable pressure nozzle to obtain droplets;
iii) cooling the droplets to induce solidification and particle formation;
iv) separating the obtained particles;
v) subjecting the particles to a conditioning step;
is directed towards.

In a fourth aspect, the invention provides a method of preparing the claimed spray congealed particles, comprising the steps of:
i) heating the mannitol until completely melted;
ii) spraying molten mannitol into a spray congealing chamber by a suitable pressure nozzle to obtain droplets;
iii) cooling the droplets to induce solidification and particle formation;
iv) separating the particles obtained; and v) subjecting the particles to a conditioning step.
is directed towards.

In a fifth aspect, the invention provides:
The present invention relates to a pharmaceutical composition in the form of a dry powder for inhalation, comprising carrier particles according to the invention and one or more active ingredients.

In a sixth aspect, the invention relates to a dry powder inhaler filled with a dry powder pharmaceutical composition as described above.

In a seventh aspect, the invention provides a method of manufacturing a pharmaceutical composition as described above, said method comprising the step of mixing carrier particles of the invention with one or more active ingredients in a high shear mixer. Relating to a method, including.

In a further aspect, the invention is also directed to a package comprising a dry powder formulation and a dry powder inhaler according to the invention.

DEFINITIONS Unless otherwise specified, "active drug", "active ingredient", "active" and "active substance", "active compound" and The term "therapeutic agent" is used synonymously.
The term "micron" is used as a synonym for "micrometer".

Generally, particle size is quantified by measuring the characteristic equivalent spherical diameter, known as the volume diameter, by laser diffraction.
Particle size can also be quantified by measuring mass diameter using appropriate equipment and techniques known to those skilled in the art, such as sieving.
The volume diameter (VD) is related to the mass diameter (MD) by the density of the particles (assuming size is independent of the density of the particles).
Alternatively, particle size can be expressed in terms of volumetric diameter. In particular, the particle size distribution is determined by i) the volume median diameter (VMD) corresponding to the diameter of 50% weight percent of the particles, e.g. VD), for example, d(v0.1) and d(v0.9).

The term "microparticles" preferably refers to particles having a median volume diameter of less than 20 microns, more preferably less than 15 microns, made from physiologically acceptable excipients and/or lubricants or antiseptics. Refers to particles made from additives with adhesive properties, or mixtures thereof.

The term "good flow properties" refers to a formulation that is easy to handle during manufacturing processes and that allows for accurate and reproducible administration of therapeutically effective doses.

Flow characteristics can be evaluated by measuring the Carr index; a Carr index of less than 25 is typically used to indicate good flow characteristics.
Alternatively, flow characteristics can be evaluated by measuring the flow function coefficient (ffc) with a shear cell module of a powder rheometer.
Depending on the ffc value, the powder can be hardened, (ffc≦1), highly agglomerated (ffc 1-2), agglomerated (ffc 2-4), easily flowing (ffc 4-10), and free-flowing (ffc≧10). It can be classified into
Values above 10 are generally considered to be free-flowing powders and exhibit good flow properties.

The expression "good homogeneity" means a formulation which, when mixed, has a content uniformity of the active ingredient, expressed in relative standard deviation (RSD), of less than 5%.

The expression "physically stable in the device prior to use" means that the active particles are substantially separated and/or exfoliated from the surface of the carrier particles, both during dry powder manufacture and in the delivery device prior to use. means a formulation that does not.

The expression "respirable fraction" means an indication of the percentage of active ingredient particles that will reach the deep lungs of a patient.

The respirable fraction, also called the fine particle fraction (FPF), is generally collected in a suitable in vitro device, typically a Multistage Cascade Impactor or a Multi Stage Liquid Impinger. ) (MLSI), Fast Screening Impactor (FSI) or Next Generation Impactor (NGI) according to the procedures reported in the common pharmacopoeia. It is calculated by the ratio of the respirable dose to the irradiated (emitted) dose.

The irradiation dose is calculated from the cumulative deposition of drug at the device stage, while the respirable dose (particulate dose) is calculated from the deposition at stages corresponding to particles with a diameter <5.0 microns.
The person skilled in the art must adjust other parameters such as inspiratory flow rate according to the guidelines reported in the General Pharmacopoeia.
A respirable fraction greater than 30% is indicative of good inhalation performance.

The term "therapeutically amount" means an amount of active ingredient that provides the desired biological effect when delivered to the lungs via the dry powder formulations described herein.

"Single dose" means the amount of active ingredient administered by inhalation at one time upon actuation of the inhaler.

"Actuation" means release of the active ingredient from the device by a single activation (eg, mechanical or exhalation).

The definition of a "substantially high single therapeutically effective amount" means that the nominal dose is greater than or equal to 800 micrograms (μg).

The term "high shear mixer" means a mixer in which a rotor or impeller, along with a stationary component known as a stator, is used in any of the vessels containing the powders to be mixed to create shear.

The term "mannitol" refers to the three polymorphic forms of mannitol: alpha, beta and delta. The β type is thermodynamically stable at temperatures of 20°C or higher.
Form δ is the lowest melting form of mannitol. The δ form is thermodynamically unstable and spontaneously converts to the more thermodynamically stable β form. The polymorphic transition from δ to β is caused, for example, by moisture.

FIG. 1 is a schematic diagram of a spray coagulation device. It is a SEM photograph of mannitol particles. Figure 2 is a WAXS pattern (stability test) of spray solidified mannitol over a period of 6 months. FIG. 2 is a WAXS pattern of spray-coagulated mannitol after preparation and conditioning. WAXS pattern after preparation and conditioning of spray-coagulated mannitol (enlarged view). This is an optical microscope photograph.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to spray congealed particles made of mannitol for use as a carrier for dry powder formulations for inhalation.
Spray congealing, also known as spray cooling, is a solvent-free method of converting a melt into well-defined spherical particles.
A typical schematic diagram of the spray-coagulation device is reported in Figure 1:
The molten sample is fed from a heated liquid container (1) to a heated nozzle (2), which sprays the sample into a coagulation chamber (3).
The heated nozzle and heated container are connected to compressed gas supply lines (4) and (5).
Air is sent to the top of the coagulation chamber (3) via an inlet HEPA (High Efficiency Particulate Air) filter (6) connected to a heat exchanger (7) and a chiller unit (8).
Air from the chamber (3) is exhausted through an outlet HEPA filter (9) and a fan (10) to an exhaust outlet (11).
The dry particles are recovered from the bottom of the coagulation chamber (3) via an outlet conduit (12) fed with compressed gas supplied from gas supply lines (13) and (14).
It is also possible to use other similar devices working on the same principle.

Mannitol is utilized in view of the fact that, contrary to other sugars such as lactose, no decomposition occurs during melting.

All particles should have a particle size, expressed in mass or volumetric diameter, in the range of 10 to 300 micrometers, preferably 20 to 280 micrometers, and more preferably 30 to 250 micrometers.

In a preferred embodiment of the invention, the particle size distribution of the carrier particles, when expressed as volumetric diameter, satisfies the following parameters:
d(v,0.1) is between 25 and 45 microns, d(v,0.5) is between 70 and 110 microns, and d(v,0.9) is between 150 and 45 microns. Included between 220 microns.

The width of the particle size distribution of the carrier particles, expressed in span, may advantageously be comprised between 1.3 and 2.2, preferably between 1.6 and 2.0.
According to Chew et al J Pharm Pharmaceut Sci 2002, 5, 162-168, the span corresponds to d(v, 0.9) - d(v, 0.1)/d(v, 0.5) .

Shape factors are used to characterize the shape of carrier particles of the present invention.
The carrier particles of the invention are therefore characterized by a shape factor comprised between 0.80 and 1.00, preferably between 0.90 and 1.00, more preferably between 0.95 and 1.00. Can be attached.

The shape factor is determined by the following equation as reported in Kumar S et al Curr Appl. Phys. Influence of metal powder shape on drag coefficient in a spray jet, 2009, 9, 678-682.
SF=1/RN
Here, RN indicates the roundness of the particle and is calculated by applying the following formula.
RN=p ² /4πA
Here, p and A are the average circumference and area values of 10 spherical particles, respectively, measured from scanning electron microscopy (SEM) images.

Alternatively, average circumference and area may be measured by optical microscopy.
Kumar S et al reported that the shape factor (SF) of the circle was 1.00.
Furthermore, although it has been reported that deviation from 1 leads to particle irregularity, particles with an SF value exceeding 0.8 can be considered to have a spherical shape.
In an exemplary embodiment, the produced carrier particles exhibited a shape factor of 0.986 as measured by Malvern Morphology G3 Ver 8.12 (Malvern Instruments Inc, Pennsylvania, USA).

Scanning electron microscopy (SEM) or optical microscopy can also be used to qualitatively evaluate the properties of the powder microparticles of the present invention, such as the shape of the particles and their surface morphology.

The carrier particles of the present invention exhibit improved flow properties, which can be measured, for example, with an FT4 powder rheometer (Freeman Technology, Tewkesbury, United Kingdom). The carrier particles of the invention are therefore characterized by an ffc value of greater than 10, typically between 14 and 16.

A number of other methods may be used to determine the properties of the carrier particles of the invention, such as true density, apparent density, and tapped density, and specific surface area.
The true density of the particles of the invention can be determined by helium hydrometry (hydrometer: AccuPyc II 1340, Micromeritics, Norcross, GA, USA) according to the following procedure:
Perform 20 purges at 19.5 psi and perform 5 analyzes at 19.5 psi with an equilibration rate of 0.0050 psi/min. The volume of the particles is measured, allowing calculation of particle density.
Typically, the true density is comprised between 1.3 and 1.6 g/cm ³ , preferably between 1.4 and 1.5 g/cm ³ .

Apparent density and tap density can be determined according to known methods.
For example, insert the sample into a 10 mL cylinder to 70-90% volume (note the exact weight and height within the cylinder).
The apparent bulk density (ABD) was determined using the following formula.
ABD=M/V0 (unit: g/mL)
Here, M is the weight of the sample and V0 is the initial volume of the sample in the cylinder.
Typically, the apparent bulk density is between 0.55 and 0.75 g/ml, preferably between 0.6 and 0.7 g/ml.

A stepwise number of taps of 10, 40, 50, 100, 300, 250, and 500 was applied, and the bulk volume of the corresponding number of taps was registered. If there was no change in height between 250 and 500 taps, the analysis was terminated after a total of 1250 taps. If a change is observed, add 1250 taps until equilibrium is reached.
Tap bulk density (TBD) was measured using the following formula.
TBD=M/Vt (unit: g/mL)
where M is the weight of the sample and Vt is the final volume of the sample in the cylinder.
Typically, the tap bulk density is comprised between 0.7 and 0.9 g/ml, preferably between 0.75 and 0.85 g/ml.

The Carr index can be calculated from IBD and TBD using the following formula.
Carr index = 100 x (TBD-IBD)/TBD (unit: %)
Typically, values were found to be much lower than 25, indicating that the carrier particles of the present invention were endowed with good flow properties.

The specific surface area can be determined by the Brunauer-Emmett-Teller (BET) nitrogen adsorption method according to known procedures.
The specific surface area of the carrier particles of the invention is comprised between 0.09 and 0.26 m ² /g, preferably between 0.10 and 0.20 m ² /g.

Surprisingly, pharmaceutical formulations containing carrier particles of the present invention can exhibit good aerosol performance without the use of fine excipient particles or fine additives. Furthermore, when mixing is carried out with a high shear mixer and short mixing times (equivalent to or less than 20 minutes), the aforementioned formulations have a high homogeneity of active ingredient, e.g. Quite high doses can be administered.
However, better uniformity could be achieved by subjecting the powder to longer mixing times using a conventional mixer.
Said optimal properties are a result of the method used to prepare the carrier particles.
The invention is therefore directed to a method of preparing the carrier particles of the invention, comprising the following steps:
i) heating the mannitol until completely melted;
ii) spraying molten mannitol into the spray coagulation chamber (3) by a pressure nozzle (2) to obtain droplets;
iii) cooling the droplets to induce solidification and particle formation;
iv) separating the particles obtained; and v) subjecting the particles to a conditioning step.

Mannitol is commercially available and each of its crystalline polymorphs (α, β, δ) and mixtures thereof, as well as amorphous and/or crystalline forms, and mixtures thereof can be used.

Spray congealing devices are commercially available, for example from ProCepT (Zelzate, Belgium).

Advantageously, in step i) the mannitol is heated under vacuum to a temperature of at least 185°C, preferably from 190 to 200°C.

In step ii) a bi-fluid nozzle can be used as a suitable nozzle.
Alternatively, other types of noses such as ultrasonic atomizers or rotary atomizers may be used to advantage.
Also, parameters related to nozzle type, internal diameter, pressure, and spray rate are adjusted by those skilled in the art depending on the batch size.
Typically, to obtain carrier particles having a particle size as claimed, the internal diameter of the two-fluid nozzle is 1.2 mm and the spray rate is in the range 18.3 to 21.5 g/min. adjusted to.
The nozzle air is adjusted to 5 l/min, corresponding to a pressure of 0.44 bar.

Cooling of the droplets in step 3) could be achieved by adding ambient temperature or cooling air during atomization at temperatures above -10 to -20°C.
In some devices, spray-melt solidification of particles could be achieved by injecting droplets into liquid nitrogen.

In step iv) the particles are separated from the gas stream, for example with a cyclone and/or a filter bag.
During solidification, the formation of the metastable δ form of mannitol takes place, so the particles of step v) are subjected to a conditioning step to convert the metastable form into the stable β form.
Preferably, the conditioning step is carried out by exposing the powder to a relative humidity of 90-97%, preferably 93%, for 12-48 hours, preferably 24 hours at room temperature in a closed chamber.
The desired humidity environment can be obtained with a saturated salt solution of potassium sulfate or potassium nitrate, preferably potassium nitrate.

The transition from the δ to the β form can be monitored by DSC or WAXS analysis according to procedures known to those skilled in the art.
Once all δ forms change to a more stable polymorphism, no further changes can be observed.

Wide-angle X-ray (WAXS) scattering can be used to measure the crystallinity and polymorphic morphology of powder samples. The measurements are carried out at room temperature using a point focusing camera system S3-MICRO camera (Bruker AXS GmbH, Germany). The sample is filled into a glass capillary with a diameter of 2 mm and analyzed at 30 counts/s for 600 seconds with constant rotation (9 rpm/min).
The sample is filled into a 2 mm diameter glass capillary and analyzed under constant rotation (9 rpm/min) for 600 seconds at 30 counts/sec.
The WAXS results after conditioning can reveal the disappearance of the characteristic Bragg peak of the δ type at about 22° and the appearance of the most prominent Bragg peak of the β type at about 23°.
In this case, it can be concluded that the selected conditioning procedure was successful in producing the desired δ to β polymorphic transition.

Alternatively, a differential scanning calorimeter (DSC 204F1 Phoenix®, Netzsch GmbH, Selb, Germany) with the following settings can be used for solid state determination.
-10 to 12 mg sample mass (n=3)
- Closed aluminum pan with holes in the lid - Heating from 25°C to 200°C at a heating rate of 10°C/min using pure nitrogen as purging gas at a flow rate of 20 mL/min.

The mannitol particles exist in substantially crystalline form.
The degree of crystallinity, expressed as % by weight of crystalline particles relative to the total weight of the particles, is higher than 90%, preferably higher than 95%.
Crystallinity and its degree are determined using X-ray powder diffraction or other techniques known to those skilled in the art, such as differential scanning calorimetry (DSC), wide-angle X-ray scattering (WAXS) or microcalorimetry. obtain.

It was found that the carrier particles after conditioning are physically stable for at least 6 months at room temperature, providing a stable formulation.
The invention is therefore also directed to pharmaceutical compositions in the form of a dry powder for inhalation, comprising the carrier particles of the invention in physical admixture with one or more active ingredients.

The active ingredient can be virtually any pharmaceutically active compound that can be administered by inhalation in dry powder form.
That is, in order for an active substance to be inhalable, i.e. to be able to pass into the deep lungs such as the terminal and respiratory bronchi, alveolar ducts and sacs, the average particle size (measured as mass average diameter) must be It should be at most about 10 microns, such as 1-10 microns, preferably 1-6 microns.
Such micronized particles can be prepared in a manner known per se, for example by micronization, controlled precipitation from selected solvents, spray drying, supercritical fluids or WO2004/073827, WO2008/155570, WO2008/ 114052 and WO2010/007447.

The therapeutic amount of the active substance may vary within wide limits, depending on the nature of the active substance, the type and severity of the condition being treated, and the condition of the patient in need of treatment.
Typically, the active agent particles are added to the carrier particles of the invention according to known procedures, preferably by mixing in a high shear mixer.
Representative high shear mixers are P100 and P300 (Diosna GmbH, Germany), Roto Mix (IMA, Italy) and CyclomixTM (Hosokawa Micron Group Ltd, Japan).
In particular, the rotation speed of the mixer and the mixing time should be adjusted by the person skilled in the art to obtain a good uniformity of the distribution of the active ingredient in the formulation.

Typically, a mixing time of at least 5 minutes and 100-500 r.p.m. p. m speed, preferably 100-250 r.m. p. Applying a mixing time of 20 minutes at a speed of m, excellent uniformity of the distribution of the active ingredient is achieved in the high shear mixer.

By way of example, active ingredients include terbutaline, reproterol, salbutamol, salmeterol, formoterol, carmoterol, milbeterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambuterol, broxaterol, epinephrine, isoprenaline or hexoprenaline or salts and/or solvates thereof. short-acting and long-acting β2 receptor antagonists such as tiotropium, ipratropium, oxitropium, oxybutynin, acridinium, trospium, glycopyrronium, or compounds known by the codes GSK 573719 and GSK 1160274; Short-acting and long-acting anticholinergic agents such as salts and/or solvates; bifunctional muscarinic antagonist-β2 agonist (MABA) compounds for inhalation such as GSK 961081; such as ONO-6818 and MK339; Neutrophil elastase inhibitors; p38 map kinase inhibitors such as VX-702, SB-681323 and GW-856553; butixocalt, rofleponide, flunisolido budesonide, ciclesonide, mometasone and its esters, i.e. furoate, fluticasone and its esters, i.e. Short-acting and long-acting corticosteroids such as propionic acid and furoate, beclomethasone and its esters, i.e. propionic acid, loteprednol or triamcinolone acetonide and its solvates; androlast, irurasucast, pranlukast, imitrodast , leukotriene antagonists such as seratrodast, zileuton, zafirlukast, montelukast; phosphodiesterase inhibitors such as filaminist, piclamilast, roflumilast; PAF-inhibitors such as apafant, lorapafant or israpafant; analgesics, morphine, fentanyl, pentazocine, buprenorphine, May be selected from analgesics such as pethidine, tilidine, or methadone; potency agents such as sildenafil, alprostadil or phentolamine; or a pharmaceutically acceptable derivative or salt of any of the aforementioned compounds or classes of compounds. .

As long as any of these compounds has a chiral center, the compounds can be used in optically pure form or can be provided as diastereomeric or racemic mixtures.

Dry powder formulations also contain as active ingredients antibiotics such as ciprofloxacin, levofloxacin and colistin, tobramycin, amikacin and gentamicin; proteins such as insulin and alpha 1-antitrypsin; antivirals such as zanamivir and ribavirin. may contain antifungal agents such as itraconazole, and phosphodiesterase (PDE)-5 inhibitors such as sildenafil and tadalafil.

Preferably, carrier particles of the invention and bifunctional muscarinic antagonist-β2 agonist (MABA) compounds, neutrophil elastase inhibitors, p38 map kinase inhibitors, short-acting and long-acting corticosteroids, and phosphodiesterase inhibitors.

The concentration of active ingredient in the powder formulation will depend on the shot weight of the formulation delivered upon actuation of the inhaler.
For example, considering an expected single dose of 800 micrograms, if the shot weight of the formulation delivered upon actuation of the inhaler is 10 mg, this would correspond to a concentration of active ingredient of 8% w/w. Probably.
Similarly, for a shot weight of 20 mg, the concentration of active ingredient would be 4% w/v.

In preferred embodiments, dry powder formulations comprising carrier particles of the present invention are particularly useful for administering active ingredients delivered in a single dose per actuation of the inhaler, ranging from 800 micrograms to 1 mg.

Although it is not essential to achieve good aerosol performance, the powder formulation may also be finely divided with a median volume diameter of less than 20 microns, more advantageously less than 15 microns, preferably less than 10 microns. A fraction of particles may be included.

Said microparticles may be made of physiologically acceptable excipients as defined above and also from the class of anti-adhesion agents such as amino acids, for example leucine or isoleucine, or from magnesium stearate, stearyl fumarate. It may be made with additives selected from the class of lubricants such as sodium acid, stearyl alcohol, stearic acid, sucrose monopalmitate, etc.

In certain embodiments, microparticles may be composed of particles of a physiologically acceptable excipient and particles of an additive in any ratio, prepared according to the teachings of WO 01/78695.

In another embodiment, the microparticles may be comprised of a mixture of 90-99.5% by weight of particles of alpha-lactose monohydrate and 0.5-10% by weight of magnesium stearate, wherein: At least 90% of the particles have a volume diameter of less than 12 microns, with the volume median diameter of the particles falling between 4 and 6 microns.

The microparticles can be added to the formulation and mixed according to known methods.

Dry powder formulations for inhalation containing carrier particles of the present invention can be utilized in any dry powder inhaler.
Dry powder inhalers are primarily used for i) single-dose (unit-dose) inhalers for single divided doses of the active compound; ii) for single-dose inhalers sufficient for longer treatment cycles; It can be divided into pre-metered multi-dose inhalers or reservoir inhalers, which are preloaded with a quantity of active principles.

Dry powder formulations may be presented in unit dosage form. Dry powder compositions for topical delivery to the lungs by inhalation may be provided, for example, in capsules and cartridges of gelatin, or in blisters of laminated aluminum foil, for example, for use in an inhaler or pneumoperitoneum. may be done.

The dry powder formulation for inhalation according to the invention is particularly suitable for multi-dose dry powder inhalers comprising a reservoir, from which individual therapeutic doses can be withdrawn on demand via actuation of the device. .

A preferred multi-dose device is an inhaler as described in WO 2004/012801, in particular from the first line of page 1 to the last line of page 39.
Other multiple dose devices that may be used are, for example, GlaxoSmithKline's ELLIPTA ^™ or DISKUS ^™ , AstraZeneca's TURBOHALER ^™ , Schering's TWISTHALER ^™ and Innovata's CLICKHALER ^™ .
A commercially available example of a single-dose device is GlaxoSmithKline's ROTOHALER ^TM
and Boehringer Ingelheim's HANDIHALER ^TM .

The invention will be explained in detail by the following examples.
Example 1 Preparation of mannitol carrier particles of the present invention
Mannitol Pearlitol 300DC was purchased from Roquette (France).
A spray coagulation device available from ProCepT (Belgium) was used.
Three different samples were prepared (60 g, 2 x 500 g comprising of 4 times 125g).
Mannitol was heated under vacuum at 200°C until completely melted, and cooled air (temperature set point chiller -20°C) in a chamber at -7°C to -10°C was passed through a two-fluid nozzle with an inner diameter of 1.2 mm. chiller -20°C) and placed in a solidification chamber. The particles obtained (yield: approximately 45%) were separated from the gas stream in a cyclone.

The formation of δ-mannitol during spray solidification raised concerns about the stability of the final particles.
In fact, the δ form is a metastable polymorph of mannitol with two stable polymorphisms (α and β).
The results of a one-month stability test of selected spray-congealed batches showed that the δ form detected after WAXS was converted to the stable β or α form over time (FIG. 3).
However, the δ form could be successfully converted to stable β-mannitol by a post-spray-coagulation conditioning step (24 hours at 93% RH set with a saturated salt solution of potassium nitrate in a closed chamber) (Figures 4 and 5).
After conditioning, the material remains stable for up to 6 months (Figure 3).

Particle morphology was investigated using a scanning electron microscope (SEM) (Zeiss Ultra 55, Zeiss, Oberkochen, Germany) operating at 5 kV.
Before analysis, samples were mounted on carbon tape and gold-palladium was sputtered (Figure 2).
Shape factor analysis was performed as follows.
Samples of spray-solidified powder were isolated with a graded spatula (sample 19 ^mm ) and aliquots were loaded into a Morphology G3 sample holder (light microscopy image analysis system, Malvern Morphology G3 Ver. 8.12) and controlled using a dedicated dispersion chamber. It was dispersed on a special slide glass with pressure (1 bar).

Image analysis was performed using a 5× objective on the selected area (circular area with a radius of 25 mm) to ensure at least 20,000 particles were measured.
Measurement parameters were set to acquire individual particles for shape analysis, and any sampling anomalies, i.e., multiple particles were removed by a software filter.
The roundness factor (RN) was determined using the formula RN=p2/4πA. Here p is the perimeter and A is the area.
Particle shape factor (PSF) was calculated by the Morphology software using equation 1/RN (this factor is called HS Circularity in Malvern Morphology terminology).
The powder exhibited a uniform spherical morphology as shown by optical microscopy and SEM photographs (Figures 2 and 6).
Particle shape factor (PSF) determined by image analysis of ˜40,000 individual particles gave an average value of 0.986, confirming the spherical morphology of the particles.

The physical state was investigated by WAXS at room temperature using a point focusing camera system S3-MICRO camera (Bruker AXS GmbH, Germany).
Samples were filled into 2 mm diameter glass capillaries and analyzed under constant rotation (9 rpm/min) for 600 s at 30 counts/s.
The WAXS results show that the peak pattern of the sample after conditioning is a mixture of α and β polymorphs (β mannitol is generated from δ mannitol), mainly α (Burger at al., Journal of Pharmaceutical Science, 2000, Energy/temperature It was found that this corresponds to the diagram and compression behavior of the polymorphs of D-mannitol).

Their micromeritics properties were reported according to the following method.
Particle size was determined by laser diffraction using an R1 lens (Sympatec HELOS).
Powder samples were distributed in two measurement conditions using an air pressure of 0.5 and 3 bar (Sympatec RODOS), respectively, and sampled at a speed of 5 m/s from a temperature- and humidity-controlled dosing unit (Sympatec ASPIROS). .
The average values of d[v, 10], d[v, 50], and d[v, 90] were calculated from three measurements.
Span was calculated using the following formula:
Span = [d(v,0.9)-d(v,0.1)]/d(v,0.5)
The specific surface area of mannitol particles was investigated using Micromeritics Tristar II 3020 (Norcross, USA).
All samples were vacuum dried at 25°C for 2 days using a Micromeritics VacPrep 061 degas unit (Norcross, USA).
Measurements were carried out using nitrogen adsorption and desorption isotherms at the temperature of liquid N ₂ (-196° C.). Brunauer, Emmett, and Teller (BET) (Emmett, 1936) adsorption theory was used to calculate the specific surface area. At that time, a pressure range of 0.05 to 0.30 normalized to the saturation pressure of the adsorbate was used.
As a result of using 1.5 g of powder, the BET correlation coefficient was 0.999 or more, demonstrating the applicability of this method. Each measurement was performed three times.
True density was measured by helium specific gravity measurement (AccuPyc II 1340, Micromeritics, USA).
Powder samples were accurately weighed and their volumes measured five consecutive times using 20 gas purges at 19.5 psi and an equilibrium rate of 0.005 psi/min.
Particle density was calculated as the ratio of sample mass to volume.
The characteristics of the tree batches are reported in Table 1.

Example 2 - Preparation of carrier particles of the invention 3-Cyclopropylmethoxy-4-[(methanesulfonyl)-amino]-benzoic acid 1-[(S)-1-[(3-cyclopropylmethoxy-4- Difluoromethoxy)phenyl]-2-[(3,5-dichloro-1-oxy)-4-pyridinyl]ethyl ester compound, hereinafter referred to as CHF6001, was prepared according to the method disclosed in WO2010/089107.

Mannitol particles were prepared as reported in Example 1.
CHF6001 formulations (25 g size batches) containing 4% w/w drug were prepared by mixing in a high shear mixer (Hosokawa Lab Cyclomix, Japan) for 20 minutes at 100 rpm or 250 rpm.
The homogeneity of the prepared mixture was checked at the end of the mixing procedure.
For each formulation, 10 samples (20-60 mg each) were taken from different spots on the powder bed.
Each sample was dissolved in 50 mL of the appropriate solvent (CH ₃ CN/water 60:40 v/v solution) and drug quantification was performed by HPLC-UV.
Homogeneity was assumed to be a coefficient of variation (calculated as the percentage of the ratio of the standard deviation of 10 measurements to the mean value) of less than 5%.
Assays are expressed as % of the theoretical content of the indicated amount.
The results are reported in Table 2.

Example 3 - In vitro Aerodynamic Performance The powder formulation of Example 3 showed aerosol performance after loading into a multi-dose dry powder inhaler, described in WO 2004/012801 and known as NEXThaler®. characterized by.
The average formulation shot weight depends on the density of the powder and is around 20 mg for this formulation.
The nominal strength of the test formulation (4% w/w drug loading) corresponds to 800 μg/20 mg/shot.
In vitro aerodynamic evaluation was performed using a Next Generation Impactor (NGI, Copley Scientific, UK) equipped with a USP induction port, pre-separator, seven impaction stages and a final micro-orifice collector.
After assembly was complete, the NGI was connected to a vacuum pump and the flow rate through the impactor was measured with a mass flow meter.
The critical flow rate (P ₃ /P ₂ ratio) was ≦0.5 at a sampling flow rate of 60 mL/min.
After connecting the device to the impactor through a gas-tight rubber port, the vacuum pump was activated for 4 seconds at a flow rate of 60 L/min so that 4 L of air was drawn through the device according to Ph.Eur.8.0, 2.9.18.
The drug CHF6001 deposited on each stage of the impactor was dispensed into the introduction port (including the mouthpiece - 50 mL), the pre-separator (100 mL), and the solvent CH ₃ CN:H ₂ O (60: 40% v/v) was used to recover from NGI. All samples were analyzed by HPLC-UV.
The aerodynamic particle size distribution is based on two actuations from the NEXThaler®, a multi-dose device described in WO 2004/012801, specifically from the first line of page 1 to the last line of page 39, respectively. Four liters of air (corresponding to an inhalation time of 4 seconds) was sampled.
Aerodynamic performance was evaluated by calculation:
- Emitted dose (ED): obtained as the sum of the amount of drug recovered in all parts of the impactor expressed in μg and indicating its proportion to the nominal dose.
- Particulate mass (FPM): the amount of drug with a cut-off diameter of less than 5 μm, calculated by interpolation according to the European Pharmacopoeia (Ph.Eur.8.0, 2.9.18.), in μg.
- Particulate fraction (FPF) calculated as the ratio of FPM to ED and expressed in percentage.
- Mean Mass Aerodynamic Diameter (MMAD), calculated as the median of the distribution of particle mass in the air over the aerodynamic diameter.
Aerosol performance results are reported in Table 3.

認識できるように、すべての調製物で良好なエアロゾル性能が得られ、ＦＰＦは４０％よりも有意に高かった。
放出線量のパーセンテージに関する優れた値が得られた。
ＣＨＦ６００１を、同じショットの公称用量（８００ｇ／２０ｍｇ）のベクロメタゾンジプロピオン酸エステルに置き換えても、放出線量の割合について同様の結果が得られた。

As can be seen, good aerosol performance was obtained for all formulations, with FPF significantly higher than 40%.
Excellent values for the percentage of emitted dose were obtained.
Replacement of CHF6001 with beclomethasone dipropionate at the same shot's nominal dose (800 g/20 mg) yielded similar results in terms of percent emitted dose.

Claims (11)

A pharmaceutical composition comprising spray coagulated carrier particles consisting of mannitol physically mixed with one or more active ingredients, the composition comprising:
the pharmaceutical composition is in the form of a dry powder for inhalation;
The pharmaceutical composition is formulated such that one or more active ingredients are delivered in a single dose ranging from 800 micrograms to 1 mg per actuation of the inhaler during use;
the particles have a mass diameter in the range of 30 to 300 micrometers;
the particles have a shape factor comprised between 0.80 and 1.15;
The particles can be obtained by a method comprising the following steps:
i) heating the mannitol until completely melted;
ii) spraying molten mannitol into a spray solidification chamber by a pressure nozzle to obtain droplets;
iii) cooling the droplets to induce solidification and particle formation;
iv) separating the obtained particles; and
v) subjecting the particles to a conditioning step. The pharmaceutical composition according to claim 1 , wherein the particles have a shape factor between 0.90 and 1.10. The pharmaceutical composition according to claim 1 or 2, wherein the particles have a shape factor between 0.95 and 1.05. Pharmaceutical composition according to any one of claims 1 to 3, wherein the particles have a mass diameter between 30 and 280 micrometers. A pharmaceutical composition according to any one of claims 1 to 4, wherein the particles have a mass diameter between 30 and 250 micrometers. Pharmaceutical composition according to any one of claims 1 to 5 , wherein the particles have a specific surface area comprised between 0.09 and 0.26 m ² /g. Pharmaceutical composition according to any one of claims 1 to 6 , wherein the particles have a true density comprised between 1.3 and 1.6 g/cm ³ . 8. The conditioning step according to any one of claims 1 to 7, wherein the conditioning step is carried out by exposing the powder to a relative humidity of 90 to 97% for 12 to 48 hours at room temperature in a closed chamber. Pharmaceutical composition . A method of preparing a pharmaceutical composition according to any one of claims 1 to 8 , said method comprising the step of mixing the atomized solidified particles with one or more active ingredients in a high shear mixer. ,Method. A dry powder inhaler filled with a pharmaceutical composition according to any one of claims 1 to 8 . A package comprising a pharmaceutical composition according to any one of claims 1 to 8 and a dry powder inhaler.

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